This application is a revision to grant RF1AG051556-01 entitled ?Interdisciplinary Research to Understand the Interplay of Diabetes, Cerebrovascular disease and Alzheimer's disease?. The main goal of this revision proposal is to study whether hyperglycemia and diabetes status (type 2 diabetes [diabetes] and pre-diabetes, compared with normal glucose tolerance [NGT]), are associated with increased accumulation of tau aggregates in the brain, one of the culprits of Alzheimer's disease (AD), ascertained with tau positron emission tomography (PET) using the ligand 18F-THK-5351, in a community-based sample of middle aged Caribbean- Hispanics with a mean age of 63 years. We will also explore whether brain tau mediates the association between diabetes status and memory impairment, the main early clinical manifestation of AD, how tau interacts with brain A? and cerebrovascular disease (CVD), and whether tau is correlated with brain physiology examined as the default mode network (DMN). Many studies have reported an association of diabetes with a higher risk of amnestic mild cognitive impairment (MCI) and late onset Alzheimer's dementia (LOAD), clinical manifestations of AD. However, the causality and mechanisms of this association have not been established. Animal studies examining the relation of diabetes with AD suggest that the main culprit may be tau phosphorylation rather than A? deposition. Thus, we propose to add tau PET imaging with the ligand 18F-THK- 5351 to the ongoing funded parent grant of A? PET imaging with 18F-Florbetaben PET in 200 middle aged Hispanics with concurrent brain magnetic resonance imaging (MRI), and assessment of cognition and diabetes status, at 2 time points, 24 months apart. Our primary aim is to compare the amount of tau accumulation, measured with 18F-THK-5351, in medial temporal and inferior temporal cortex, cross-sectionally and longitudinally (with an interval of 2 years) across categories of diabetes status (pre-diabetes, diabetes, and normal glucose tolerance [NGT]). We will also examine glycemia continuously using Hemoglobin A1c (HbA1c) as an exposure, controlling for diabetes treatment. Secondary aim 1 is to explore whether differences in tau in medial temporal and inferior temporal cortex among participants with diabetes, pre-diabetes, and NGT, mediate the association of diabetes and pre-diabetes with worse memory performance. We will also examine HbA1c as a continuous exposure measure. Secondary aim 2 is to explore the interaction of tau in medial temporal and inferior temporal cortex with (a) brain fibrillar A? and (b) cerebrovascular disease (CVD) in mediating the association of diabetes and pre-diabetes with memory impairment. We will also examine HbA1c as a continuous exposure measure. Secondary aim 3 is to examine whether the presence of tau in medial temporal and inferior temporal cortex mediates the association of diabetes categories and hyperglycemia with the abnormalities in the DMN,29 ascertained with Blood Oxygen Level Dependent (BOLD) MRI imaging. !